Endocrine Abstracts

Objectives: Limited and conflicting data exist regarding mutational profiles and clinical responses to tyrosine-kinase inhibitors (TKI) in advanced radioiodine refractory thyroid cancer (RAIR-TC). The role of BRAF/RAS mutational status on progression-free survival (PFS) in patients treated with lenvatinib is controversial. This study aims to assess the impact of genetic profiles on clinical responses to lenvatinib in RAIR-TC.

Materials and methods: We analyzed data from 49 patients with RAIR-TC surgically treated and followed at the University Hospital of Pisa who performed lenvatinib as first-line TKI therapy between 2012 and 2023. Nucleic acids were extracted from FFPE tissues and analyzed using NGS. TERT promoter and TP53 mutations were assessed via digital PCR. Response to Lenvatinib was assessed by CT scans according to RECIST.

Results: Males and females were equally distributed and median age at diagnosis was 60.5 years (IQR 50.7-68.4). PTC and FTC accounted for about 80% of all cases, while 10% had PDTC. About 30% of patients had distant metastases at diagnosis. The median duration of Lenvatinib therapy was 23.1 months (IQR 8-38.5). Genetic alterations were found in 39/49 cases (79.6%). A single driver mutation was found in 10/49 cases (20.4%): BRAF in 3/49 (6.1%), RAS in 6/49 (12.2%), and RET/PTC rearrangement in 1/49 (2%). Twenty-two cases (44.9%) had a driver mutation co-occurring with TERT or TP53 mutations. Seven cases lacked driver mutations but showed TERT mutation in 6/49 (12.2%) cases and TP53 in 1/49 (2%). Median overall survival (OS) was 9.5 years (IQR 6.2-15.2), while median PFS was 16 months (IQR 5.8-29.6). When dividing patients in group 1 (single driver mutation: point mutations or gene rearrangements), group 2 (driver mutation co-occurring with TERT or TP53) and group 3 (no driver mutations, with or without additional mutations), OS did not significantly differ among the three groups (P = 0.373). However, molecular profile significantly influenced PFS. Group 1 had better PFS compared to group 2 and 3 (P = 0.038). In multivariate analysis, the absence of driver mutations was the only factor significantly associated with worse PFS (HR 3.095 – 95%CI 1.065-8.998; P = 0.038).

Conclusions: In patients with RAIR-TC treated with lenvatinib as first-line TKI, the mutational status did not significantly impact on OS. However, the absence of driver mutations, regardless of TERT or TP53 mutations, was independently associated with a worse PFS.